This study was approved by the Medical Ethics Committee of Shandong Provincial Hospital (SWYX:2022-449). Clinical and laboratory procedures were conducted after obtaining written informed consent from all participants. All procedures adhered to the principles outlined in the Helsinki Declaration.

Peripheral blood DNA extraction: Peripheral blood samples were collected from the proband and his parents using EDTA-anticoagulated tubes. Genomic DNA was extracted from the samples using the QIAamp DNA Blood Midi KIT (Qiagen, Germany) in accordance with the manufacturer’s instructions and quantified using both a NanoDrop spectrophotometer and a Qubit fluorometer (Thermo Fisher Scientific, Waltham, MA, United States).

NGS analysis: WES was performed on the proband’s genomic DNA, which was sent to Hangzhou Dean Medical Laboratory Center for bioinformatics analysis. The analysis targeted coding regions of 5,075 genes associated with hereditary diseases, with a specific focus on genes linked to inherited bone diseases and chondrosarcoma. High-quality variants were identified through filtering and screening processes, followed by annotation using major genetic databases, including NCBI, dbSNP, OMIM, ESP, ExAC, ClinVar, and Thousand Genomes. The pathogenicity of identified variants was further evaluated using predictive bioinformatics tools such as SIFT, PolyPhen-2, and MutationTaster.

Polymerase chain reaction (PCR) amplification and Sanger sequencing were conducted to confirm the candidate mutation. Primers were designed to target the identified mutation site, and PCR amplification was performed on the genomic region containing the suspected mutation. The PCR products were stored appropriately before being subjected to Sanger sequencing using an ABI 3130xl genetic analyzer. Sequencing results were aligned and compared with NCBI reference sequences using Chromas software to confirm the mutation.

Conservation across species was assessed using the T-Coffee tool (https://www.ebi.ac.uk/jdispatcher/msa/tcoffee/). For the protein modeling, wild-type protein models were generated using the SWISS-MODEL tool (https://swissmodel.expasy.org/). The spatial structure and altered residue of the mutant protein were visualized using PyMOL software to assess the structural impact of the identified mutation.

Through WES technology, we can identify all variants (including point mutations and small indels) in the exons of 5,075 genes and their adjacent ±20 bp intronic regions in the patient. The detection is performed using a standardized target region capture sequencing platform, with quality control metrics as follows: an average coverage of 98.99% and an average sequencing depth of 124.86. Subsequently, the identified variants are annotated and compared with disease-related databases such as Online Mendelian Inheritance in Man (OMIM)and Human Phenotype Ontology (HPO) to determine if they match known clinical phenotypes. This process helps us understand whether the discovered genetic variants are associated with specific diseases or symptoms.

NGS revealed that the proband carried a pathogenic heterozygous missense mutation in the COL2A1 gene, specifically in exon 13 at c.823C > T (p.Arg275Cys) (Table 1). No other pathogenic mutations, suspected pathogenic variants, or variants of unknown clinical significance were identified in genes related to chondrosarcoma. Sanger sequencing confirmed the presence of the same COL2A1 mutation in both the proband and his father. The heterozygous missense mutation (c.823C > T) in exon 13 of the COL2A1 gene resulted in the substitution of arginine with cysteine at the p.Arg275 position (p.Arg275Cys). The proband’s mother tested negative for this mutation (Table 2; Figures 5, 6).

Conservation analysis indicated that the arginine residue at position p.Arg275 is highly conserved across multiple species, underscoring its potential functional importance (Table 3). Structural modeling revealed that the substitution of arginine with cysteine at residue 275 led to alterations in the protein structure (Figure 7). The c.823C > T variant’s pathogenicity was assessed via bioinformatic tools, including SIFT, PolyPhen-2, and MutationTaster. Referring to the HumanDiv database, Polyphen-2 scores ≥0.957 suggest the amino acid substitution is probably damaging; scores between 0.453 and 0.956 indicate the substitution is possibly damaging; and scores ≤0.452 imply the substitution is benign. SIFT scores span from 0 to 1, with amino acid substitution scores < 0.05 indicating a prediction of deleteriousness, and scores ≥0.05 suggesting the substitution is tolerated. The c.823C > T (p. Arg275Cys) in the COL2A1 gene was predicted to be deleterious: MutationTaster (0.999, disease-causing), SIFT (0.010, damaging), and PolyPhen-2 (1.000, probably damaging) (Figure 8).

Adult DDH must be differentiated from other conditions that cause hip pain, such as avascular necrosis of the femoral head (ANFH), hip OA, and ankylosing spondylitis (AS). When imaging reveals multiple loose bodies, it is essential to distinguish SC-associated findings from pigmented villonodular synovitis (PVNS).

When AD is accompanied by cystic degeneration of the femoral head, it should be differentiated from ANFH (Deng, 2014). Cystic degeneration in AD develops secondary to the underlying biomechanical abnormalities and often involves both the femoral head and the acetabulum, particularly in the weight-bearing areas (Deng, 2014). These cysts are typically adjacent to the joint surface, with smooth, well-defined margins and sclerotic edges. In some cases, a vacuum phenomenon may be observed (Deng, 2014). The morphology of the femoral head in AD remains largely preserved, though joint space narrowing and joint subluxation are common (Deng, 2014). In contrast, ANFH primarily affects the femoral head, with well-developed hip sockets and cystic degeneration restricted to the femoral head (Liu et al., 2010). Acetabular involvement is uncommon in ANFH, and the cystic lesions often exhibit mixed densities, poorly defined boundaries, and variable sizes, sometimes appearing as crescent-shaped or fissured areas (Liu et al., 2010). In advanced stages, the femoral head may fracture, collapse, and deform, with joint space narrowing occurring only in later stages (Deng, 2014). Joint subluxation is rare in ANFH, and patients often have a history of corticosteroid use, alcohol abuse, or trauma (Deng, 2014).

In late stages, AD may lead to secondary OA, which requires differentiation from primary degenerative hip OA. While both conditions share similar pathological mechanisms, the presence of AD serves as a precursor in secondary OA (Deng, 2014). AD-related OA tends to present at a younger age and is more common in females (Deng, 2014). In such cases, osteogenesis, sclerosis, and cystic degeneration predominantly affect the acetabulum, with larger cystic lesions and common joint subluxation (Deng, 2014). Conversely, primary degenerative OA is associated with normal acetabular development, occurs more frequently in males, and is characterized by bone hyperplasia and smaller cystic changes primarily involving the femoral head. In primary OA, the cysts are often chiseled and small, and joint subluxation is uncommon (Deng, 2014).

AS is more common in adolescents and mainly affects axial joints, particularly the sacroiliac joints and spine, often causing structural changes and strongly associated with the HLA-B27 (Pedersen and Maksymowych, 2019). The proband sought medical attention due to bilateral hip pain, and an initial MRI of the sacroiliac joints revealed findings suggestive of sacroiliitis, which may have led the attending physician to consider AS as a possible diagnosis. However, it is essential to carefully evaluate the patient’s symptoms, laboratory findings, and imaging data to arrive at an accurate diagnosis. From a symptomatic perspective, low back pain is a hallmark feature of AS, often presenting early in the disease. However, in the proband’s case, low back pain was not a predominant symptom, and he did not report severe nocturnal pain. His symptoms worsened with activity and did not improve with rest, which is inconsistent with inflammatory back pain typically seen in AS. Additionally, the patient tested negative for HLA-B27, further reducing the likelihood of an AS diagnosis. The imaging findings also did not support AS. Although MRI initially indicated “sacroiliitis,” further analysis revealed that the sacroiliac joint surfaces were relatively smooth, and the observed inflammatory edema signal was inconsistent with sacroiliac arthritis. The sacroiliitis-like changes might instead be attributed to mechanical stress on the sacroiliac joints, potentially caused by prolonged use of crutches and poor posture, such as leaning forward. Therefore, a diagnosis of AS or spondyloarthritis could not be confirmed.

PVNS, also known as tenosynovial giant cell tumor (TGCT), is a benign lesion characterized by synovial villous nodular hyperplasia and hemosiderin deposition (Li et al., 2021). Malignant transformation and metastasis of PVNS are rare (Li et al., 2021). The clinical presentations of PVNS and SC are similar, with both conditions initially manifesting as hip pain and reduced range of motion (Startzman et al., 2016). Conservative treatment often fails to relieve symptoms in either disease (Xie et al., 2015). However, imaging studies can help differentiate the two conditions. PVNS is typically characterized by a slightly high-density soft tissue mass around the joint on CT, with varying degrees of adjacent bone destruction. The soft tissue mass in PVNS is often separated by fibrous septa (Han et al., 2010). In contrast, the CT scan of the proband’s hip joint revealed multiple high-density foci consistent with calcified nodules, without any evidence of bone destruction. These findings effectively ruled out PVNS as a diagnosis in this case.

Although extensive research has explored the genetic underpinnings of DDH, no definitive susceptibility genes have been identified (Wen et al., 2023). In a systematic review, Wen et al. pointed out that the genes most closely associated with DDH are CX3CR1, ASPN, COL1A1, HOX, and GDF5, with GDF5 receiving the most attention in the literature (Wen et al., 2023). In addition to these well-studied susceptibility genes, Wen et al. also summarized that animal models have implicated other genes, including TENM3, UFSP2, and WISP2 in the development of DDH (Wen et al., 2023). Futhermore, epigenetic changes also contribute to the pathogenesis of DDH. According to Wen et al., these include abnormal methylation of gene promoters, the altered expression of microRNAs such as miR-1-3p, miR-129-5p, and miR-140, and dysregulation of the long non-coding RNA (lncRNA) H19 (Wen et al., 2023).

Researchers have proposed that two distinct genetic pathways may underlie the development of DDH. The first involves genes responsible for the formation and development of acetabular cartilage and bone, while the second regulates genes involved in the development of the hip joint capsule and surrounding soft tissues (Wynne-Davies, 1970). Current research primarily focuses on these two pathways to better understand the molecular regulatory mechanisms involved in DDH (Zhao et al., 2023). Thus, identifying these genetic patterns and susceptibility genes is essential for clarifying the complex pathogenesis of DDH and holds potential for improving early detection, diagnosis, and treatment (Zhao et al., 2023). Advances in genetic research have highlighted the importance of identifying candidate and susceptibility genes for DDH (Zhao et al., 2023). In parallel, the development of genetic screening tools, including intrauterine diagnostic techniques, offers promising avenues for early detection and prenatal diagnosis (Zhao et al., 2023). Early genetic diagnosis could facilitate timely interventions, potentially improving patient outcomes (Zhao et al., 2023).

For children with a high risk of DDH but without obvious symptoms, the risk of developing DDH can be assessed by detecting these specific gene mutations (Agenbag et al., 2020). The detection of the COL2A1 gene can be done through direct cycle sequencing and NGS methods (Agenbag et al., 2020). Although the COL2A1 gene contains 54 exons, direct cycle sequencing is still a viable method for variant detection due to its relatively small overall size (Agenbag et al., 2020). However, NGS offers a better choice in terms of efficiency and coverage. NGS can sequence one or more target genes or even the entire exon group at the same time, thereby accurately identifying gene mutations that lead to hereditary diseases (Agenbag et al., 2020).

The earlier DDH is detected, the better the treatment outcome (Wang et al., 2023). Studies have shown that the effectiveness of treating DDH at the age of 8 is not superior to not treating it (Thomas, 2015). Therefore, early detection and diagnosis are key to treatment. Clinical screening methods for DDH in newborns and infants include physical examination, ultrasonography at 6 weeks, and X-ray screening at 4–6 months (Ji et al., 2022). These clinical screening methods have a low detection rate for DDH patients who later need hip joint replacement surgery, and there is a risk of over-treatment (Paton, 2017). Therefore, genetic screening should be supplemented for high-risk infants (Ji et al., 2022). For children without related gene mutations, regular testing and physical correction should be adopted as much as possible to avoid excessive treatment; for children with related gene mutations, long-term follow-up monitoring should be carried out simultaneously with treatment to determine the abnormal development of the hip joint (Ji et al., 2022).

The main purpose of early treatment of DDH is to restore the concentric relationship between the acetabulum and the femoral head, usually based on non-surgical treatment (Wang et al., 2023). When the age increases or the closed reduction correction is not possible, surgical treatment is needed to improve gait, alleviate pain, and prolong the lifespan of the hip joint (Wang et al., 2023). Most untreated adult DDH has a poor prognosis, while early diagnosis and treatment can improve disease outcomes, reduce the probability of needing surgical treatment later, and alleviate the burden of the disease on patients, families, and society (Wang et al., 2023).

In the present case, secondary SC was associated with congenital acetabular dysplasia, affecting both the hip and knee joints. This report provides a concise overview of research advances in the genetics of SC.

Extensive research has been conducted to understand the pathogenesis of SC. Traditionally, SC has been considered to result from chondroid metaplasia of the joint synovium (Brucher et al., 2014). However, several studies have highlighted a possible association between SC and chromosomal abnormalities or gene mutations. Sciot et al. reported a case of SC involving clonal chromosomal changes and proposed that SC could be classified as a true neoplastic disorder (Sciot et al., 1998). Similarly, Mertens et al. analyzed the cytogenetics of four SC cases and identified the loss of chromosomal band 10q26 and rearrangements in 1p13 and 12q13, further supporting the theory of clonal proliferation in SC (Mertens et al., 1996). In a study by Totoki et al., an FN1-ACVR2A in-frame gene fusion was identified in one case of SC during a genomic investigation of benign and malignant cartilaginous neoplasms (Totoki et al., 2014). When analyzing seven additional cases of SC, the same gene fusion was detected in one other case. Subsequent studies by Amary et al. (2019) and Agaram et al. (2020) confirmed the presence of FN1 and/or ACVR2A gene rearrangements in SC using fluorescence in situ hybridization (FISH) and RNA sequencing. Additionally, Fukutani et al. (2022) identified a homozygous mutation (C/C genotype) in the Gli1 gene (rs2228226 G > C) in two cases of SC involving the temporomandibular joint. These findings suggest a genetic component in the development of SC.

This study has some limitations. Firstly, clinical whole exome high-throughput sequencing cannot fully cover certain genes or gene regions that are highly repetitive, low complexity, or pseudogene regions. The detection scope does not include genomic structural variations (such as large heterozygous deletions, duplications, and inversion rearrangements), large heterozygous insertion mutations, or mutations located in regulatory regions or deep intronic regions. Secondly, although these imaging findings provided sufficient evidence to establish a definitive diagnosis of acetabular dysplasia with overlapping SC, unfortunately, surgical specimens were not collected for pathological confirmation.